Herpesviruses cause latent infections that persist for the lifetime of the host and these viruses have developed mechanisms to counteract host defenses so as to allow the virus to persist. Using sophisticated computer programs we are identifying herpesvirus genes that may have cellular homologs. These genes are being expressed in various systems to determine how the genes may interact with host cell proteins, including those of the immune system, to influence the course of infection. Identification of these genes may help define new targets for antiviral therapy or new insights into modulating the immune system. Epstein-Barr virus (EBV) has a membrane glycoprotein gp42, encoded by the BZLF2 gene, that has homology to members of the C-type lectin family. In collaboration with Immunex Corporation, we have constructed a soluble fusion protein containing the human IgG Fc domain linked to the extracellular domain of BZLF2. The fusion protein containing the extracellular domain of BZLF2 was shown to bind to the human MHC class II HLA-DR beta chain and inhibit the outgrowth of EBV transformed B cells in vitro. In addition, this fusion protein inhibited antigen presentation and reduced generation of antigen-specific cytotoxic T lymphocytes in mixed lymphocyte cultures. In collaboration with Immunex, we have shown that herpesvirus saimiri (HVS) encodes a novel cytokine, viral interleukin 17. Viral IL17 increases the level of other interleukins (IL6 and IL8). A similar gene, murine IL17, was identified in the mouse genome and a receptor for IL17 was located and sequenced. This receptor is unrelated to any previously identified cytokine receptor. HVS also encodes another protein, the ORF14 protein, that was found to bind to the MHC class II HLA- DR beta chain. The ORF14 protein was found to stimulate proliferation of T cells.